Abstract
Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and the assembly defect, confirming the causal role of the variant. Our report on the second family affected by an NDUFAF4 variant further characterizes the phenotypic spectrum and sheds light into the role of NDUFAF4 in mitochondrial complex I biogenesis.
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Acknowledgements
We thank the mitochondrial diagnostics group (muscle lab, cell culture lab and DNA lab) of the Radboud Center for Mitochondrial Medicine (RCMM) at the Translational Metabolic Laboratory, Radboud UMC for excellent technical assistance. We would like to acknowledge the Genome Technology Center at the Radboud UMC and BGI Copenhagen for providing the exome sequencing service. This project was funded by the European Commission (FP7-PEOPLE-ITN. GA. 317433). Part of this work was financed by a grant obtained from the United Mitochondrial Disease Foundation (UMDF). FB was supported by a fellowship of the German Research Foundation/Deutsche Forschungsgemeinschaft (BA 5758/1-1).
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Informed consent for diagnostic and research studies was obtained for all subjects in accordance with the Declaration of Helsinki and following the regulations of the local medical ethics committee.
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Baertling, F., Sánchez-Caballero, L., van den Brand, M. et al. NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect. Eur J Hum Genet 25, 1273–1277 (2017). https://doi.org/10.1038/ejhg.2017.133
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DOI: https://doi.org/10.1038/ejhg.2017.133
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